Athletes are exposed to a wide range of physiological and psychological stresses and responses that are influenced by and, in turn, impact on athletic performance. Athletes often train at very high levels with inadequate rest and eat too few calories, which in combination could compromise their immune systems and expose them to infection and injury.
Athletes have been shown to have antibody responses to pneumococcal vaccine equivalent to sedentary individuals (51), suggesting that their immune system is not impaired. There is little doubt that acute intense exercise suppresses the immune system and causes an “open window” of opportunity for pathogens and microorganisms to infect the athlete (40,48). Moderate exercise training has been shown to improve immune function and lower infections (40,41,45,48). Although the “open window” is transient (40), its period may be extended by overtraining (45), preexercise stress (45), exercising during the incubation phase of an infection (10), malnutrition (12,41), mental stress (41,47), rapid weight loss (41), or poor hygiene (41).
It has been shown that many athletes eat diets comprised of too few calories, particularly some essential nutrients such as fats, iron, zinc, and calcium (18). These macro-and micro-nutrient deficiencies may compromise the immune system. Athletes produce more reactive oxygen-radicals than do nonathletes, exposing them to increased oxidative stress (36).
The role of lipids in the immune responses to exercise has been under-appreciated. This is due in large part to the failure to recognize the importance of glycogen sparing by fat oxidation and nutritionists’ beliefs that a high-fat diet may compromise the immune system. Recent studies have established the potential role of fat oxidation in glycogen sparing and, in fact, have shown that increasing the fat intake in athletes can increase exercise endurance and in some athletes maximal aerobic power (46,57,58). The intramuscular fat stores are in droplets that are in contact with the mitochondria. These fat stores become depleted during endurance exercise (70) and are increased on a high-fat diet (17). The conclusion from these studies is that reducing fat intake to very low levels compromises exercise performance due to low intramuscular stores of fat.
Our purpose is to show how a low-fat diet may compromise the immune system and how a higher-fat diet may improve it. Consideration will be given to exercise and dietary lipids, and how these two factors affect the immune system.
Dietary Lipid Intake
The total caloric expenditure in athletes is two- to three-fold that of sedentary individuals due to the increased level of daily exercise in training and performing. Studies in both male and female runners have reported that their caloric intakes are only 65–75% of their estimated caloric expenditure and are low in fat (18). Increasing the fat intake of runners from 15 to 42% increased their total caloric intake by 17–26% and brought them near energy balance (18). Although many athletes purposely reduce their fat intake and total caloric intake to maintain a low body weight, increasing fat from 15 to 42%, or total calories by 25%, for 8 wk, did not result in an increase in body weight or adiposity (18,32). Protein intake in the diets of most athletes is sufficient to meet the demand (0.8 g·kg−1·d−1) (18). The percentage of fat in the diet can be increased to 42%, with a protein intake of 20%, and a carbohydrate intake of 38% can be maintained. This is sufficient to maintain intramuscular glycogen stores on a calorically balanced diet. Conversely, in athletes on high-carbohydrate diets (65%), with 20% protein, the fat intake (15%) on a low-calorie diet is not likely to maintain intramuscular fat stores. The intake of vitamins A, E, C, calcium, zinc, and iron are low on a low-fat diet, particularly in women, compared with a high-fat diet in runners (18).
Effect of Exercise on Immune Competency
Acute exercise is a “stressor” as it results in increased metabolism, excess heat production, and widespread physiological adjustments that impact on immune function. Nutritional imbalances result in depletion of intramuscular energy stores of glycogen and fats. The combination of these over-stresses and reduced energy stores may result in increased stress to the immune system during exercise training and performance.
Differential mobilization of leukocyte subsets during exercise has been reported (24) and can be explained by changes observed in the subpopulations of peripheral blood mononuclear (PBMN) cells. The ratio of T-helper/T-suppressor (CD4+/CD8+) is reduced to varying degrees based on the intensity of physical activity. Long-term running may induce some change in lymphocyte subpopulations (23). Chronic submaximal exercise induces increased mobilization of neutrophils and decreased mobilization of lymphocytes and decreases the absolute and relative number of neutrophils at rest (11).
Although the number of lymphocytes in the blood may be elevated by physical exercise, their functions may be impaired. In vitro impairment of responses to mitogens has been associated with a variety of immune deficiencies in vivo, such as changes in CD4+/CD8+ ratios, decreases in the production of IL-2, increases in prostaglandin E2 (PGE2) levels, improved macrophage function, etc. The reduction in the CD4+/CD8+ ratio may decrease DNA synthetic responses. This reduced response may be sufficient to allow microorganisms and viruses time to evade early immunological recognition and establish ongoing infection in runners. Generally, moderate intensity exercise may decrease the proliferative response by 35–50% (39). A consistent depression in mitogenesis 2 h after an exercise bout has been reported (34).
Cytokines and inflammatory response.
Exercise can alter the release of numerous cytokines and modulate their receptor systems. Such changes may trigger inflammatory and acute phase responses. Inflammation in athletes may be caused by mechanical stress, local ischemia, and/or free radical generation in the active skeletal muscle. After high-intensity exercise, the immune system becomes involved in tissue repair processes. Suppression of IL-2 and increases in IL-1 and TNF-α production are reported after exercise (11,52,60). Physical exercise, including eccentric muscle contractions, induces increases in the production of monokines.
Exercise and the inflammatory response.
It is becoming increasingly evident that most of the distinguishing features of a classical inflammatory response are detectable in an exercising individual, namely mobilization and activation of granulocytes, lymphocytes, and monocytes; release of inflammatory factors and soluble mediators; involvement of acute phase reactants; and activation of the complement and other reactive humoral cascade systems (56).
Inflammation results from the recruitment to a given tissue or organ and the activation of leukocytes, among which the monocyte-macrophages play a major role. These phagocytic cells produce high levels of reactive oxygen species (ROS) and cytokines. Whereas both ROS and cytokines have the potential to regulate the expression of heat shock (HS)/stress proteins (HSP), it appears that these proteins in turn have the ability to protect cells and tissues from the deleterious effects of inflammation (20). In vivo, HS protects organs against a number of lesions associated with the increased production of ROS and or cytokines. HSP (hsp70 in particular) may also exert protective effects on the immune system by contributing to when cells are exposed to different types of stress. A single exercise bout in humans is able to increase the steady state concentration of hsp70 mRNA but is probably not sufficient to have an effect on the already high basal level of this protein (20). Specific fatty acids can lower the levels of certain pro-inflammatory cytokines. These lipids may have a protective role to defend against the inflammatory responses caused by exercise.
Strenuous exercise is accompanied by an increase in circulating pro-inflammatory and inflammation-responsive cytokines, having some similarities with the response to sepsis and trauma. The sequential release of TNF-α, IL-1β, IL-6, and IL-1 receptor antagonist (IL-1ra) in the blood is comparable to that observed in relation to bacterial diseases. Eccentric exercise is associated with an increase in serum IL-6 concentrations and is significantly correlated with the concentration of creatine kinase (CK) in the following days, whereas no changes are found after concentric exercise; this demonstrates a close association between exercise-induced muscle damage and increased serum levels of IL-6.
On the basis of data showing that endotoxin-inducible interferon-γ (IFN-γ) production is virtually abrogated for a short period after excessive exercise, the rigorous regulatory blockade of one of the ways of IFN-γ induction may be critically involved in causing the transient immunosuppression after exhaustive exercise (42). Cytokine inhibitors and antiinflammatory cytokines restrict the magnitude and duration of the inflammatory response to exercise.
Acute phase proteins (APP).
APPs are glycoprotein molecules found in serum during acute infection or inflammation and increase after intense endurance exercise. The concentration of serum c-reactive protein (CRP), the major APP, increases six-fold after 2–3 h of running and may remain elevated up to 3 d after the run. CRP levels may reflect the combined effects of both intensity and duration. Other APPs, such as protease inhibitors and iron binding proteins, are also elevated after endurance running and some may remain elevated for up to 6 d.
Higher resting levels for serum protease inhibitors in well-trained athletes suggest that higher activity of protease inhibitors may limit proteolytic activity in muscle and connective tissue after exercise. APPs are generally released in response to infection, inflammation, and injury, such as that induced by prolonged exercise. APP release is stimulated by certain cytokines that have been shown to increase during exercise. APPs such as C-reactive protein and serum amyloid A protein have exciting potential use as stable biochemical markers of disease in claudication (64,65).
Neuroendocrine factors released in situations of stress, such as intense exercise, are suggested to be partly responsible for the exercise-induced changes in the immune system. Most immunosuppressive responses induced by intense exercise correlate with increases in circulating cortisol (4,35). It has been established that the leucocytosis induced by exercise is mediated by catecholamines and glucocorticoids (37), and the specific immune response of lymphocytes is also mediated by adrenaline, glucocorticoids, β-endorphin, and other stress hormones (16).
Exercise is known to activate the pituitary-adrenocortical axis to increase cortisol levels. Muscular exercise increases the concentrations of a number of stress hormones in the blood, including adrenaline, noradrenaline, growth hormone, beta-endorphins, and cortisol, whereas the concentration of insulin decreases slightly (25). Adrenaline and noradrenaline may be responsible for the immediate effects of exercise on lymphocyte subpopulations and cytotoxic activities. The magnitude of the increase in cortisol was substantially lower in trained subjects exercising at the same absolute workload as their untrained counterparts (58).
Dietary Fat, Exercise, and Immune Function
Lipids modulate immune function by several factors and mediators (9,44). Both the quantity and type of dietary lipids are known to have modulatory effects on the cellular immune system at biochemical and molecular levels. The mechanisms by which lipids modulate immune function may involve several factors, including the production and expression of cytokines (7,69). Dietary ω-6 lipids generally increase the levels of pro-inflammatory cytokines and inflammatory prostaglandins (PGs), whereas ω-3 lipids may decrease the levels of these cytokines and inflammatory PGs (68).
Cytokine-mediated “reprogramming” of metabolism is a mechanism that ensures an adequate supply of nutrients for proliferation of lymphocyte and macrophage populations, antibody production, and hepatic synthesis of acute phase proteins. Pro-inflammatory cytokines have been linked to altered nutrient uptake and utilization. Anabolic processes are interrupted, and companion catabolic activities are amplified by certain pro-inflammatory cytokines. Changing dietary fat consumption may alter the immune system and hormone levels as lipids being components of biomembranes, serve as precursors for certain steroid hormones and PGs, have a role in regulating eicosanoid synthesis, and interact directly with cellular activation processes. The other known effects of ω-6 and ω-3 fatty acids are associated with the alteration in eicosanoid synthesis of PGs, thromboxanes (TXs), and leukotrienes (LTs). Under normal conditions, these eicosanoids are produced by the oxidation of arachidonic acid (AA).
In general, the eicosanoids produced from AA are in the 2- and 4-series, such as PGE2, PGI2, TXA2, and LTB4. PGE2 has a number of pro-inflammatory effects. In addition, PGs and other eicosanoids play a role in regulating the differentiation and functions of T-cells, B-cells, NK cells, and macrophages. PUFAs with 20-carbons are preferentially incorporated into tissue phospholipids with a relatively high specificity for AA (2,19). It is generally the PUFAs of the ω-6 series that increase the levels of pro-inflammatory cytokines and PGs. Perhaps the types of fats in the diet may be beneficial in preventing the exercise-induced rise in pro-inflammatory cytokines. As lipids are powerful mediators of the immune system, and they exert their effects on cytokines, hormones, etc., the immunosuppressive effects of strenuous exercise may be modulated by dietary fats.
In vivo, many cytokines increase serum triglycerides (TG) by increasing very-low-density lipoprotein production (15). Interferons (IFNs) increase TG predominantly by decreasing lipoprotein lipase activity and TG clearance. IL-6 induces many of the endocrinologic and metabolic changes found in catabolic states and thus may mediate some of the metabolic effects previously ascribed to other cytokines (61). Cytokine-mediated alterations can explain the inability of adequate dietary nitrogen and calories to result in lean tissue repletion. As the production of several cytokines is under negative control by PGE2, synthesis of PGE2 is decreased after consumption of ω-3 polyunsaturated fatty acids (PUFAs). Exercise causes some injuries in muscle and joints that may increase PGE2 levels (59). Both the quantity and type of dietary fat are known to influence the level of PGE2.
As lipids are known to have immunomodulatory role, it thus may be possible to blunt the inflammatory effects of exercise by providing dietary lipids that have a tendency to lower the inflammatory effect. The observed decreases in the level of pro-inflammatory cytokines on a high-fat diet may be explained in part by the low levels of PUFA in the diets of the runners who participated in this study (66). In women runners, both medium- and high-fat diets significantly increased the number of natural killer (NK) cells and IL-2 levels over levels on a low-fat diet. Saturated and monounsaturated fat levels are higher compared with PUFAs in all diets in this study (66). Recently, monounsaturated fatty acids (MUFAs) have been reported to be less inflammatory when compared to ω-6 fatty acid. For example, as olive oil, rich in monounsaturated fatty acids, e.g., oleic acid (18:1), when compared with ω-6 rich corn oil.
Plasma IL-2 levels have been shown to be higher in male than female runners and decreased in men with increased dietary fat (67). The plasma IL-6 level was lower after an exhaustive endurance run and decreased with an increase in the percent of dietary fat intake. Increasing the level of dietary fat had no adverse effects on the level of plasma pro-inflammatory cytokines in runners (67). Both exercise and a high-fat diet increase the level of IL-2 and lowered the level of IL-6, suggesting that it is possible to modulate the level of specific pro-inflammatory cytokines through increased fat intake, thus off-setting the pro-inflammatory effects of exercise.
Plasma cortisol levels are higher in women on a high-fat diet compared with the low-fat diet (15% fat), but not in men. In male runners, the plasma cortisol level decreased on a medium-fat diet compared with a low-fat diet at rest and after exercise (8). In male runners, the PGE2 level is higher when runners are on a low-fat diet compared with when they are on the higher-fat diet. Data have shown that the combined effects of high-fat diets and exercise are different from the effect of dietary fat and exercise analyzed separately. No significant increase in plasma cortisol, PGE2, and IFN-γ levels are observed on a high-fat diet in well-trained athletes after an exhaustive endurance run. It appears that increasing dietary fat can increase endurance run time without adverse effects on plasma cortisol, PGE2, and IFN-γ.
Exercise and antioxidant defense system.
Research evidence has accumulated in the past decade that strenuous aerobic exercise is associated with oxidative stress and tissue damage. It is therefore conceivable that dietary supplementation with specific antioxidants would be beneficial (22). During severe oxidative stress, the enzymatic and nonenzymatic antioxidant systems of skeletal muscle are not able to cope with the massive free radical formation, which results in an increase in lipid peroxidation. Exercise and training, however, appear to augment the body’s antioxidant defense system (5). Whether this augmented defense system can keep up with the increase in lipid peroxidation with exercise is not known. Vitamin E is reported to decrease exercise-induced lipid peroxidation. The exercise may increase superoxide anion generation in the heart, and the increase in the activity of superoxide dismutase (SOD) in skeletal muscle may be indirect evidence for exercise-induced superoxide formation.
Exercise and gene expression.
Nucleic acids are suggested to be the messengers in regulatory information transfer from the immune system to other cells (13). Exercise causes selective changes in gene expression leading to alterations in the structure and function of human skeletal muscle (49). Little is known about the specific signaling pathways that enable exercise to modulate gene regulatory events.
The activity of c-Jun NH2-terminal kinase (JNK), a signaling molecule involved in the regulation of transcription, is reported to be associated with an increased expression of its downstream nuclear target c-Jun mRNA (1). The JNK pathway may serve as a link between contractile activity and transcriptional responses in human skeletal muscle. It is believed that the induction of the fos and jun gene family of transcription factors might be at the origin of genetic events leading to the differential regulation of muscle-specific genes. The effect of a 30-min running bout in untrained subjects on the expression of the mRNAs of all members of the fos and jun gene families, including c-fos, fosB, fos Bdel, fra-1, and fra-2 as well as c-jun, junB, and junD has been investigated (50). Although the fos family members were transiently upregulated 10- to 20-fold, the induction of the jun family members was up to three-fold only. Both c-fos and c-jun mRNAs were co-induced in muscle fiber nuclei. The induction was not restricted to a particular fiber type, as expected from established muscle fiber recruitment schemes, but followed a “patchy” pattern confined to certain regions of the muscle. The signals leading to the expression of these immediate early genes are therefore unclear. The loss of muscle protein is due to an early decrease in protein synthesis rate and a later increase in protein degradation. The initial decrease in protein synthesis is a result of decreased protein translation, caused by a prolongation in the elongation rate. Decreases in mRNAs for contractile proteins usually occur after the initial fall in protein synthesis rates.
Exercise increases skeletal muscle lipoprotein lipase (LPL) expression, but the time course of this response is not known. Acute exercise preceded by four daily bouts of exercise induced a transient rise in LPL mRNA followed by rise in LPL mass, suggesting that these responses are temporally related (55). This induction of LPL gene expression may result from dynamic changes in serum catecholamines, plasma insulin, or events intrinsic to muscle contraction.
Lipids and gene expression.
The recent discovery of lipid-activatable transcription factors that regulate the genes controlling lipid metabolism and adipogenesis has provided insight into the way that organisms sense and respond to lipid levels (21,71). Ligand activation of the nuclear receptors peroxisomal proliferator-activated receptors (PPARs), PPAR-γ, regulates systemic glucose and lipids (38). PUFAs and eicosanoids bind and activate PPAR-γ. PPAR-α and -γ function in lipid homeostasis. These receptors are activated by direct binding of hypolipidemic drugs and of MUFAs and PUFAs. Upon activation, these receptors interact with a number of different genes involved in lipid metabolism (26,73). PPAR-α and PPAR-γ are shown to function as important regulators in lipid and glucose metabolism, adipocyte differentiation, inflammatory response, and energy homeostasis. PPAR-α seems to mediate its pleiotropic effects mainly through the stimulation of oxidation of lipids, whereas PPAR-γ is a key mediator of lipid storage (54). The effects of lipids and exercise on PPARs is not known at the present time.
What is the optimal regular diet and fat intake to enhance both athletic performance and immune competency and health? Low-fat high-carbohydrate diets (i.e., 60–70% of calories from carbohydrate and 15–25% of calories from fats) have traditionally been recommended to improve the health and performance of endurance athletes (57). Recent experimental data, however, suggest that very low-fat high-carbohydrate diets may not be optimal for the health of endurance athletes (3,32,66) or, in fact, for some subgroups of the general population (27).
The data on endurance athletes included runners who were training 30–60 miles·wk−1 at 60–80% of their O2max and competing at least once per week. Other studies tested cyclists, ballerinas, gymnasts, and a cross-section of team sport athletes training 1.5–2 h·d−1 4–6 d·wk−1. The studies cited for the general population evaluated sedentary subjects and other studies tested the recreational athletes training two to four times per week at moderate intensities.
Athletes in sports emphasizing leanness and/or appearance may be “fat phobic” (32,46). They fear that eating fat will increase body fat and body weight and consequently impair performance. These athletes avoid calorically dense, higher-fat foods and so consume fewer calories per day than they expend during training (32). Hypocaloric diets consumed chronically may reduce athletic performance and can negatively influence health, especially in female athletes (72). The Female Athlete Triad of disordered eating, amenorrhea, and premature osteoporosis is a potentially lethal condition thought to be, in part, the result of hypothalamic-pituitary axis dysfunction related to chronic energy depletion in female athletes (72,75). Recent data, however, suggest that these athletes need not fear fat. Short-term (from 2 wk to 3 months) experimental trials in male and female endurance athletes (3,32) have shown that, when energy demand and expenditure are high during training, daily fat intakes of 30–85% of calories maintained or increased caloric intake but did not increase body adiposity or weight or reduce athletic performance.
Very low-fat diets (<20% of daily calories) appear to blunt some of the beneficial changes endurance training ordinarily confers upon lipoproteins (6,32,62). In experimental trials of very low-fat diets, serum high density lipoprotein (HDL)-C, Apolipoprotein A1 (the protein component of HDL cholesterol, Apo A1), and the TC:HDL-C ratio more resemble those of sedentary humans than of endurance athletes (6,32,62). Furthermore, recent data on the genetics of cholesterol metabolism indicate that very low-fat diets may induce a phenotypic “shift” in those with large low-density lipoprotein (LDL) particles toward the more atherogenic small LDL particles (30,31). Large LDLs are associated with low triglycerides and high HDL-C, whereas small LDLs are associated with elevated triglycerides, low HDL-C, insulin resistance, and an increased risk of heart disease (30,31). Endurance athletes have the low triglycerides and elevated HDL-C (3,32,63) associated with larger LDL particles; thus, further study is required to evaluate the qualitative LDL response in these athletes to altered dietary fat. Accumulating data suggest that training athletes can consume significant amounts of fat over the short term without adverse effects on immune function and the traditional cardiovascular risk factors. What may be more important than the macronutrient composition of their diet, however, is whether endurance athletes’ caloric intake offsets their high regular caloric expenditure. It is clear that many athletes cannot maintain caloric balance if they avoid dietary fat; thus, their training may suffer. In addition to contributing to chronic energy depletion, particularly in female athletes, very low-fat diets in athletes have been shown to be deficient in important micronutrients (18,66). They may also lack the essential fatty acids (particularly ω-3 and ω-6) that are important for normal immune (28) and neurologic function (29). There is recent evidence that very low dietary fat is in fact detrimental to some parameters of immune function in endurance athletes (66,67). Some studies suggest that there is an increased incidence of infections in athletes (45), and another study suggests athletes take in too few calories and fats (18). These studies suggest that if athletes increased total caloric and fat intake they may be less susceptible to infections; however, we are unaware of any prospective studies that have tested this hypothesis.
Dietary fat intake has profound effects on gene expression and thus performance, health, and disease (9,28,68,69). Studies on sedentary animals and observational and epidemiological studies in sedentary humans have implicated dietary fat as a factor in cancer (colorectal, skin, pancreas, breast, prostate) (74). Based on observational and epidemiological data, without controlled experimental data, the U.S. Food & Drug Administration has stated that cancer is related to dietary fat (33). Recent prospective epidemiological data has cast doubt on the possibility of a strong relationship between dietary fat and cancer (14). Polyunsaturated fats (ω-3) may reduce cancer risk (53) and chronic exercise may be protective (43).
In the studies that demonstrated an association between high dietary fats and cancer in sedentary humans, total caloric intakes was high and resulted in obesity. Athletes rarely have caloric intakes greater than expenditure and are usually not obese. We are unaware of any studies suggesting that higher fat intake in athletes would increase their risk of cancer.
In summary, the experimental data suggest that athletes of both sexes engaging in regular, high-volume exercise can safely ingest from 30 to 50% of total daily calories as fat. Training athletes who eat higher fat diets do not gain weight or body fat, yet they are better able to compensate for the high caloric requirements of regular training. This may be particularly important for female athletes who are at risk for serious psychological, metabolic, hormonal, and skeletal consequences of chronic energy depletion. Moderate rather than very low-fat intake appears to augment the beneficial effect of endurance training on the immune system and serum lipoproteins. Athletes at least should avoid very low levels of dietary fat (<20% of daily calories) and avoid combining factors that extend the “open window” for infections such as overtraining, mental stress, poor hygiene, and caloric imbalance.
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